This invention relates to a method of use of calcium channel blocking agents, and more particularly to a method of potentiating, i.e. augmenting synergistically, the pharmacological effects of dihydropyridine derivatives in cardiac tissue.
Calcium antagonists are relatively new drugs which are used to treat coronary heart disease. Their effects are to increase the flow of blood to the heart, remove stresses on the cardiovascular system, lower blood pressure and lower heartbeat. Administration of these drugs may prevent a heart attack.
Three calcium channel blocking agents are presently being used in the United States, known generically as nifedipine (a dihydropyridine derivative), verapamil (a papaverine derivative), and diltiazem (a 1,5 benzothiazepine derivative). Nifedipine is sold under the registered trademark PROCARDIA, verapamil under the registered trademarks ISOPTIN and CALAN, and diltiazem under the registered trademark CARDIZEM.
By way of further background, diltiazem is 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methyoxyphenyl)-1,5- benzothiazepin-4(5H)-one hydrochloride. It was developed in Japan. Due to the presence of two asymmetric carbon atoms, a d-cis isomer and an l-cis isomer are known to exist. The following molecular structure illustrates this isomerism: ##STR1## In the d-cis isomer the side groups are oriented behind or below the plane of the benzothiazepine ring, whereas in the l-cis isomer the side groups are oriented above the ring. For convenience, the d-cis isomer, which is the active isomer in the method of this invention, will hereinafter be designated as "d-cis-diltiazem", and generic names of other drugs will be used.
The present invention constitutes a discovery that small dosages of d-cis-diltiazem potentiate the effects of nifedipine and other dihydropyridine derivatives and in the heart. This has very significant applications. Patients who are sensitive to nifedipine could take one-half or even one-quarter the normal dosage but receive the same benefits and additionally obtain the advantages of diltiazem as well. Diltiazem has an important antirhythm effect (i.e., prevents palpitations) which nifedipine lacks. Moreover, the combination of both drugs is believed to have a greater beneficial effect on high blood pressure than either drug alone. It will of course be recognized that smaller dosages of drugs also diminish greatly the chance of toxic side effects.
Numerous studies of the effects of calcium channel blocking agents have been reported in the literature. Reference may be made to "Symposium on Cardiovascular Disease and Calcium Antagonists", Arnold Schwartz, Guest Editor, American Journal of Cardiology, Vol. 49, No. 3, February 1982, pages 497-635, and articles acknowledged therein; and to "Calcium Channel-Blocking Drugs: A Novel Intervention for the Treatment of Cardiac Disease", Arnold Schwartz, Editor, Circulation Research Part II, Vol. 52, No. 2, February 1983, pages I-1 to I-174.
Reference may also be made to A. De Pover et al "Specific Binding Of [.sup.3 H] Nitrendipine . . . Stimulation by Diltiazem", Biochemical and Biophysical Research Communications", Vol. 108, No. 1, September 1982, pages 110-117; and to an article by A. DePover et al in Biochemical and Biophysical Research Communications, Vol. 113, No. 1, May 1983, pages 185-191.
The molecular structures of nifedipine and verapamil are reported to be as follows: ##STR2##